FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer

FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6960266/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Small cell lung cancer (SCLC) is a lethal lung malignancy which is associated with distant metastasis and chemoresistance. Limited targeted therapies further worsen disease outcomes. Single-cell and bulk RNA-sequencing (RNA-seq) datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression in human and murine SCLC tissues and cell lines was observed. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1 fl/fl ; TP53 fl/fl ; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of cancer cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the TME of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response. Small cell lung cancer FOXM1 inhibitors T cell activation chemotherapeutic resistance metastasis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryFiguresS1S19.pdf Supplementary Figures S1-S19 SupplementaryInformation.docx Supplementary Information SupplementaryFigureLegend.docx Supplementary Figure Legends Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6960266","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478933158,"identity":"386cd0ea-b5f0-4c11-a748-bbb28eaeb0b0","order_by":0,"name":"Md Arafat Khan","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Md","middleName":"Arafat","lastName":"Khan","suffix":""},{"id":478933159,"identity":"aee2875f-41c3-40ef-9103-0af05d3b0af2","order_by":1,"name":"Parvez Khan","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Parvez","middleName":"","lastName":"Khan","suffix":""},{"id":478933160,"identity":"6a7ad5f9-d4bf-4d89-a670-aef245dd864b","order_by":2,"name":"Mahek Fatima","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mahek","middleName":"","lastName":"Fatima","suffix":""},{"id":478933161,"identity":"b2e570d1-8cfc-44d0-96b6-c7311a4b0eb7","order_by":3,"name":"Asad Ur Rehman","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Asad","middleName":"Ur","lastName":"Rehman","suffix":""},{"id":478933162,"identity":"543e465f-b24e-4aad-bfc3-06091a12167a","order_by":4,"name":"Laiba Anwar","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Laiba","middleName":"","lastName":"Anwar","suffix":""},{"id":478933163,"identity":"bf0bf5a3-6fcf-4093-8682-6bcc796f551e","order_by":5,"name":"Zahraa Wajih Alsafwani","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Zahraa","middleName":"Wajih","lastName":"Alsafwani","suffix":""},{"id":478933164,"identity":"c0829af6-79bc-4431-a75f-74448724729e","order_by":6,"name":"Aatiya Ahmad","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Aatiya","middleName":"","lastName":"Ahmad","suffix":""},{"id":478933165,"identity":"d396d843-f1f3-4235-9c63-357e18c2711c","order_by":7,"name":"Mohammad Ali Abbas Zaidi","email":"","orcid":"","institution":"University of Nebraska Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Ali Abbas","lastName":"Zaidi","suffix":""},{"id":478933166,"identity":"1970d00a-29e4-495b-b8ee-25f92de328b6","order_by":8,"name":"Jesse L. 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17:25:32","extension":"html","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":240514,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/24026930c94ea7d7ffb4c0d4.html"},{"id":92536484,"identity":"00c0263c-9f23-48e3-b088-a8dd5e23ba94","added_by":"auto","created_at":"2025-09-30 17:25:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":187196,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 is overexpressed in small cell lung cancer samples.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Single cell RNA-sequencing analysis of lung cancer patient samples and normal controls showing the differential clustering of different cell types including immune, endothelial, fibroblast and epithelial cells, showing high FOXM1 in SCLC epithelial cells. (B) Single cell transcript analysis showing high FOXM1 in SCLC epithelial cells compared to different cell types of normal and LUAD samples. (C) FOXM1 expression in SCLC patient dataset (GSE149507). (D) Representative IHC images showing FOXM1 staining in SCLC tumor tissues and normal lung tissues in a tissue microarray (US Biomax, #Cat BS04116a). (E) Histological scoring of FOXM1 expression in SCLC and normal lung tissues as shown in panel D. (F) Expression of FOXM1 in association with lineage specific markers (NE or Non-NE) in SCLC cell lines. (G) FOXM1 expression in SCLC cell lines through immunoblotting. (H) FOXM1 expression in adjacent normal and RPM lung tumor tissues. Statistical analysis is from student’s t test, unpaired comparison, **** = p \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/674a57782a8dd3c451e79942.jpg"},{"id":92536775,"identity":"f1fd6809-582a-4485-a36a-d8425f1f4e9b","added_by":"auto","created_at":"2025-09-30 17:33:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":159927,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 knockdown reduces colony formation, migration and 3D spheroid growth of SCLC cells.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) shRNA-mediated conditional knockdown (KD) of FOXM1 in SBC-3 and SBC-5 cell lines. (B) FOXM1 conditional KD decreases ERK activation (p-ERK). (C-D) Representative images and quantification of colony formation in control and FOXM1 conditional KD cell line models. (E-F) Representative images of trans-well migration studies with control and FOXM1 KD, showing a significant reduction in number of migrated cells in FOXM1 KD groups. (G) 3D sphere formation images showing reduced number of spheroids formed per field of vision compared to respective controls. A high 3D sphere growth inhibitory response was observed in KD combined with cisplatin. Statistical analysis is from student’s t test, unpaired comparison, ns=non-significant, **=p\u0026lt;0.001, and **** = p \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/e6469d7637e76e6eb93b249a.jpg"},{"id":92537386,"identity":"4c3d7f53-c4c1-4b1e-9cfd-4b2d6fc63a44","added_by":"auto","created_at":"2025-09-30 17:41:31","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":259278,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 inhibitor (FOXM1i) treatment reduces cell viability, colony formation and induces apoptosis in SCLC cell lines.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) FDI-6 treatment reduces cell viability of human and murine SCLC cell lines. (B) Schematic showing the strategy of generating cisplatin resistant SCLC cell lines from RPM mice and human cell lines. (C) Comparison between naïve and cisplatin resistant RPM cell lines response towards cisplatin treatment. (D) FOXM1 expression status in Cisplatin resistant SCLC cell lines compared to their naïve counterparts. (E) FOXM1 inhibition sensitizes cisplatin resistant SBC-5 CisR cells towards cisplatin. \u0026nbsp;(F-G) Representative images of colony formation in naïve and cisplatin resistant SBC-5 cell lines after FOXM1 inhibition (student’s t test, unpaired comparison, *** = p \u0026lt;0.0008, **** = p\u0026lt; 0.0001). (H) FOXM1 inhibitor FDI-6 (5 µM for 48 h) reduces FOXM1 protein levels. (I) Flow cytometry-based analysis reveals induction of apoptosis after FOXM1 inhibition in SCLC cells. (J) Quantitation of apoptosis shown in panel I. (K) FDI-6 Treatment induces cleaved Caspase 3 (C. Caspase 3) expression in multiple cell lines of SCLC.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/c7631088e037f671ad95385f.jpg"},{"id":92537583,"identity":"b6f2594b-bbf9-484c-8770-7b0be44342f0","added_by":"auto","created_at":"2025-09-30 17:49:31","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":300165,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFDI-6 alone or in combination with cisplatin inhibited SCLC xenograft tumor growth\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e(A) Schematic showing the treatment strategy for subcutaneous xenograft study in NSG mice. (B) Representative bioluminescence images from IVIS imaging system for different treatment groups. (C) Tumor volume measurement showing differential tumor growth in the different treatment groups. (D) Representative ex vivo tumor images isolated from vehicle, FDI-6 (60mg/kg), cisplatin (2.5mg/kg) and combination (cisplatin and FDI-6) treated groups. (E) Tumor weight measurements showing FDI-6 treatment in combination with cisplatin significantly reduces tumor growth. (F) Immunohistochemical staining and quantification of xenograft tumor sections derived from mice treated as in panel E. Statistical analysis is from student’s t test, unpaired comparison, ns= non-significant, *=p\u0026lt;0.05, **=p\u0026lt;0.001, and *** = p \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/44fcebab02a21bd2b75d558f.jpg"},{"id":92536495,"identity":"ae4767d2-13fd-479f-b1c4-02cc6c143f40","added_by":"auto","created_at":"2025-09-30 17:25:31","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":335886,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 inhibition attenuates growth and metastasis in spontaneous mouse model of SCLC.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Schematic showing study design in RPM, a spontaneous mouse model of SCLC. (B) Representative IVIS bioluminescence images of RPM mice at the day of randomization (day 0 of treatment) and at the end of treatment (day 28 of treatment). (C) Quantification of whole-body bioluminescence intensity in RPM mice treated with vehicle, FDI-6 (60 mg/kg), cisplatin (2.5 mg/kg) and combination (cisplatin and FDI-6) groups. (D-E) Representative H\u0026amp;E staining and quantification of RPM mice lung tumors showing significant downregulation of tumor burden in the combination group compared to control mice. (F) Images of IHC staining of RPM lung tumor sections with FOXM1 and cleaved caspase 3 (apoptotic marker) in different treatment groups as shown in panel B. (G-H) Quantification of FOXM1 and cleaved caspase 3 IHC staining as shown in panel F. (I) Bulk RNA sequencing of vehicle and FDI-6 treated SCLC cell lines (DMS-273) showing downregulation of multiple genes associated with FOXM1. (J) Pathway analysis through gene set enrichment studies showing top modulated pathways in FDI-6 treated cells. (K) AURKB IHC staining on SBC-3 xenograft tumor tissues isolated from different treatment groups. (L) Quantification of AURKB positive cells as shown in panel K. (M) Immunoblotting analysis depicting downregulation of AURKB following FOXM1 inhibition and KD. (N) FOXM1 inhibitors reduces the chromatin binding of FOXM1 to the promoter region of AURKB. (O) FOXM1 inhibition by FDI-6 induces G2 cell cycle arrest in SCLC cells. Statistical analysis is from student’s t test, unpaired comparison, *=p\u0026lt;0.05, **=p\u0026lt;0.001, and *** = p \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/370778030a35706abbe1f3b1.jpg"},{"id":92536780,"identity":"9a5314fd-66f6-43b9-ab11-bd29b68b1191","added_by":"auto","created_at":"2025-09-30 17:33:31","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":262214,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 inhibition in combination with cisplatin potentiates T cell mediated killing of SCLC cells.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Volcano plot based on RNA-sequencing data of vehicle and FDI-6 treated SCLC cells showing that FOXM1 inhibition upregulates the expression of inflammatory cytokines. (B) Schematic showing the experimental design to study the role of FOXM1 inhibitors in T cell activation and T cell mediated cancer cell killing. (C-D) FOXM1 inhibitors (FDI-6 or NB-73) alone or in combination with cisplatin promotes T cell mediated killing of naïve SCLC cells. (E) Representative contour plots of flow cytometry analysis showing the differentiation and activation of human T cells cocultured with human SCLC cell line (SBC-5). (F-G) Quantitation of human T-cells activation data obtained from co-culture studies of human SCLC cells with T-cells as analyzed through flow cytometry under various treatment conditions. Statistical analysis is from student’s t test, unpaired comparison, *=p\u0026lt;0.05, **=p\u0026lt;0.01, *** = p \u0026lt;0.001, and **** = p \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/e3af1bf847b7af9cc45b0359.jpg"},{"id":92536500,"identity":"fe83112d-c4fd-49e8-b51c-b6893ca2e10a","added_by":"auto","created_at":"2025-09-30 17:25:31","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":248618,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFOXM1 inhibition enhances immune cell infiltration in the tumor microenvironment.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Representative immunofluorescence images of RPM mice lung tumor tissue sections stained with anti-CD8 antibody (green), anti-F4/80 (red) antibody, and DAPI (blue) under different treatment conditions. (B) Quantitation of CD8+ T-cells and F4/80+ macrophages in RPM lung tumor tissues. student’s t test, unpaired comparison, *=p\u0026lt;0.05, **=p\u0026lt;0.01, *** = p \u0026lt;0.001, and **** = p\u0026lt; 0.0001. (C) Representative images of IHC staining for anti-CD8 T and anti-F4/80 macrophages infiltrating SCLC lung tumors. (D) Quantitation of CD8+ T-cells and F4/80+ macrophages in RPM lung tumor tissues from different treatment groups. student’s t test, unpaired comparison, *=p\u0026lt;0.05, **=p\u0026lt;0.01, *** = p \u0026lt;0.001, and **** = p\u0026lt; 0.0001. (E) Schematic representation of FOXM1 modulating SCLC progression, which can be attenuated using FOXM1 inhibitors.\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/9e6db2185f37c296b00efedc.jpg"},{"id":92600330,"identity":"63cb9f51-73eb-44ea-9d14-57f27413ddc9","added_by":"auto","created_at":"2025-10-01 14:19:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2556283,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2_covered_99446b4f-cca4-46d9-ae1d-e6ecbd031870.pdf"},{"id":92536499,"identity":"1ad3267d-ac6b-4094-8a99-279d79f01f60","added_by":"auto","created_at":"2025-09-30 17:25:31","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3118824,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figures S1-S19\u003c/p\u003e","description":"","filename":"SupplementaryFiguresS1S19.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/a0c33874a24efc15bf75d2e0.pdf"},{"id":92537390,"identity":"75d91ded-a67e-47f2-bd2a-d6600798ede9","added_by":"auto","created_at":"2025-09-30 17:41:31","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":104019,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information\u003c/p\u003e","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/e6142ce3a7d362d3c71c65cb.docx"},{"id":92536487,"identity":"789e78c8-afd4-4fd7-8d12-bb72aa158798","added_by":"auto","created_at":"2025-09-30 17:25:31","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":17609,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure Legends\u003c/p\u003e","description":"","filename":"SupplementaryFigureLegend.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960266/v2/baccdcbc2430048fb3ffbb63.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Small cell lung cancer, FOXM1 inhibitors, T cell activation, chemotherapeutic resistance, metastasis","lastPublishedDoi":"10.21203/rs.3.rs-6960266/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6960266/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSmall cell lung cancer (SCLC) is a lethal lung malignancy which is associated with distant metastasis and chemoresistance. Limited targeted therapies further worsen disease outcomes. Single-cell and bulk RNA-sequencing (RNA-seq) datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression in human and murine SCLC tissues and cell lines was observed. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM:\u003cem\u003e RB1\u003c/em\u003e\u003csup\u003e\u003cem\u003efl/fl\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e; TP53\u003c/em\u003e\u003csup\u003e\u003cem\u003efl/fl\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e; LSL-MYCT58A)\u003c/em\u003e mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of cancer cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the TME of immunocompetent RPM model. This study demonstrates that FOXM1 targeting\u0026nbsp; small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.\u003c/p\u003e","manuscriptTitle":"FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-09-30 17:25:26","doi":"10.21203/rs.3.rs-6960266/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-07-01 08:59:30","doi":"10.21203/rs.3.rs-6960266/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f75dd37b-c6b2-4495-96e3-75977f2cefce","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-05T01:08:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 17:25:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-6960266","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6960266","identity":"rs-6960266","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}